Medical Treatment for High Grade Gliomas – An Overview

1
Medical Treatment for High Grade Gliomas An
Overview

• Dr Daphne Tsoi
• MBBS MSc FRACP
• Medical Oncologist
• Royal Perth Hospital
• SJOG Hospitals Subiaco, Murdoch

2
Incidence

• 1400 cases of primary brain tumour diagnosed in
  Australia each year
• Primary CNS cancers 7/100,000/year
• (Colon cancer 60/100,000/year)
• 14th most common cancer in Australia
• Highest in terms of average year lost (12 years
  per patient)

3
Average years of life lost for patients in
Australia and the UK, 2001, by cancer type
Sources Burnet et al , Australian Institute of
Health and Welfare (AIHW)
4
Glial cells
http//ovidsp.com/spb/ovidweb.cgi
Chamberlain MC et al. West J Med.
1998168114-120.
5
Glioma Grading
Chamberlain MC, et al. West J Med.
1998168114-120.
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Median Survival Importance of Histologic Grading

• Pathologic diagnosis is crucial in determining
  treatment and prognosis

1Bruce J. Available at http//www.emedicine.com.
2Hariharan S. Available at http//www.emedicine.c
om. 3DeAngelis LM. N Engl J Med. 2001344114-123.
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Primary vs Secondary GBM

• Primary GBM
• Develops de novo from glial cells
• Accounts for gt 90 of biopsied or resected cases
• Clinical history of 6 months
• Occurs in older patients (median age 60 years)

• Secondary GBM
• Develops from low-grade or anaplastic astrocytoma
• 70 of lower grade gliomas develop into
  advanced disease within 5-10 years of diagnosis
• Comprises lt 5 of GBM cases
• Occurs in younger patients (median age 45 years)

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Presentation

• Headache
• Seizure
• Motor weakness/speech deficit
• Altered personality
• Loss of memory/cognition
• Dizziness

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Investigations

• MRI
• Biopsy

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Features of Glioblastoma Multiforme

• Rapid progression
• Enhancing tumor
• Surrounding edema
• Contains tumour
• 5 multifocal

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Treatment

• Surgery
• Radiotherapy
• Chemotherapy

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Temozolomide(Temodal)

• Methylating agent
• Principal mechanism is causing damage to DNA of
  tumour cell, leading to cell death
• Taken orally, rapidly absorbed
• Penetrates the blood-brain barrier
• Dose according to body surface area
  (height/weight)

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Temozolomide Side Effects

• Tiredness / fatigue
• Nausea
• Constipation (from anti-emetics)
• Low blood counts red/white/platelets
• Particularly lymphocytes (risk of Pneumocystis
  carinii pneumonia)
• Rash

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Standard Treatment for GBM

• Radiotherapy concurrently with Temozolomide
  followed by 6 months of Temozolomide

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Phase III Study New GBM Radiation Temozolomide
Concomitant TMZ RT
Adjuvant TMZ
R
0
Wks
6
10
14
18
22
26
30
RT Alone
TMZ 75 mg/m2 PO QD for 6 weeks, then 150-200
mg/m2 PO QD on Days 1-5 every 28 days for 6
cycles
Focal RT daily30 x 200 cGytotal dose 60 Gy
PCP prophylaxis was required for patients
receiving TMZ during the concomitant phase.
Stupp R, et al. N Engl J Med. 2005352987-996.
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Phase III Study New GBM Radiation Temozolomide

• Phase III study (N 573) 2-year OS rate
  improved from 10.4 with RT alone to 26.5 with
  temozolomide

100
Median Survival
90
RT temozolomide 14.6 months
80
RT alone 12.1 months
70
60
50
Probability of OS ()
40
30
20
10
0
0
6
12
18
24
30
36
42
Months
Stupp R, et al. N Engl J Med. 2005352987-996.
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Temozolomide - indications

• Recurrence of anaplastic astrocytoma and
  glioblastoma multiforme

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Surgical Implantation of Chemotherapy Wafers
Gliadel

• BCNU-infused wafers
• implanted to tumour bed at time of surgery
• chemotherapy released to surrounding brain tissue
  over a period of 2 to 3 weeks
• Clinical trials showed survival benefit
• PBS difficulties

Gliadel? is a trademark of Guilford
Pharmaceuticals.
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Progressive Disease

• Challenges of diagnosing progressive disease
• Pseudo-progression
• increase in enhancement without tumor progression
• Especially after chemo-radiation
• First post-RT MR scan should not be used for
  treatment decisions
• Treat the patient not the scan
• Techniques to help distinguish - MRS
  (spectroscopy), PET scans, SPECT scans

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Pseudoprogression The Index Case

• Male, gross total resection for anaplastic
  ependymoma in August 97, no neurological
  deficits, pre-RT MRI
• Deterioration during/after radiation therapy
  (10/97-12/97, 65 Gy)
• Thereafter slight clinical improvement for more
  than 1 year

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Further Treatment for Progression

• Surgery
• Radiation (stereotactic radio-surgery)
• 2nd line chemotherapy

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2nd line Chemotherapy

• No consensus
• Low dose temozolomide (/- procarbazine)
• Carboplatin
• BCNU/CCNU
• Bevacizumab (/- Irinotecan)
• Clinical trials if possible

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Glioblastoma A Highly Vascular Tumour

• The vascular network formed in GBM is abnormal
• vessels are dilated, tortuous, disorganised,
  highly leaky

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Angiogenesis
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Avastin (Bevacizumab) mechanism of action
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Bevacizumab Anti-VEGF Antibody
After 4 cycles bev/irinotecan
Recurrent GBM at baseline

• Vredenburgh JJ, et al. J Clin Oncol.
  2007254722-4729.
• National Comprehensive Cancer Network guideline
  CNS cancers (V.1.2008)

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Bevacizumab for recurrent glioblastoma

• Unanswered questions
• Phase II results only
• ?changes on MRI reflect tumour shrinkage, or
  reduced swelling from stopping leaking blood
  vessels
• Concerns about rapid progression upon stopping
  treatment
• Phase III trials underway

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New drugs that failed to impress

• Erlotinib
• Enzastaurin
• Edotecarin
• Cediranib

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Approach to Patients

• Complex challenges specific to brain tumour
  patients
• Disease
• Physical impairment weakness, poor mobility,
  speech, vision
• Cognitive impairment memory, insight, judgment,
  personality, disinhibition
• Depression
• Seizures

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Approach to Patients

• Polypharmacy
• Steroids
• weight gain, elevated BSL, proximal myopathy,
  emotional lability, reversal of sleep/wake cycle
• Anticonvulsants
• Antiemetics / aperients / antibiotics
• Anticoagulants
• Medications for other medical conditions
• ?compliance

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Approach to Patients

• Financial / income source
• Family / dependents
• Transfers to frequent clinic visits
• Home modifications / hire equipments
• Carers
• burn-out, financial source

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Approach to Patients

• Multidisciplinary approach
• Neurosurgeon
• Radiation Oncologist
• Medical Oncologist
• Rehabilitation team
• Clinical specialist nurse
• Neurologist
• Endocrinologist
• OT/physio/dietitian/speech pathologist
• Community/palliative care/hospice
• Social worker
• Inpatient team
• GP

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Conclusions

• Management of GBM remains challenging with median
  survival at 9-15 months
• Survival improved by
• Resection
• Adjuvant radiotherapy plus concurrent
  chemotherapy
• Temozolomide is component of standard of care
• Promising investigational directions the use of
  targeted therapy
• Individually tailored therapy based on genetic
  profile
• Clinical trials participation should be
  considered
• Multidisciplinary team approach is paramount